G proteins are a large and diverse family of proteins. Defects in G protein signaling are implicated in a diverse variety of physiological responses to pharmaceuticals as well as in disease.
G proteins play important roles in the regulation of cell growth, differentiation, and oncogenic transformation. Agonists acting at G protein couples receptors have been implicated as oncogenes (for a review, See e.g., Gudermann et al., Nauyn-Schmiedeberg's Arch. Pharmacol., 361:345 [2000]). Research indicates that an irregularity in any GPCR pathway component can cause a physiological defect (Meij, Mol. Cell. Biochem. 157:31 [1996]). For example, mutations in components of the cell signaling cascade as well as alterations in the expression pattern of these components may result in abnormal activation of leukocytes and lymphocytes, leading to the tissue damage and destruction seen in autoimmune diseases such as rheumatoid arthritis, biliary cirrhosis, hemolytic anemia, lupus erythematosus, and thyroiditis. T cell activation is also a G protein regulated process (Aussel et al., J. Immunol. 140:215 [1988]).
Irregularities in G protein signaling also have a role in abnormal cell proliferation. Cyclic AMP stimulation of brain, thyroid, adrenal, and gonadal tissue proliferation is regulated by G proteins. Mutations in Gβ subunits have been found in growth-hormone-secreting pituitary somatotroph tumors, hyperfunctioning thyroid adenomas, and ovarian and adrenal neoplasms (Spiegel, J. Inher. Metab. Dis. 20:113 [1997]).
Genetic disorders caused by loss or gain of function mutations in G, subunits include Albright hereditary osteodystrophy, pseudohypoparathyroidism type Ia with precocious puberty, McCune-Albright syndrome, and congenital night blindness (Spiegel, supra). GPCR mutations are responsible for many diseases including color blindness, retinitis pigmentosa, congenital night blindness, nephrogenic diabetes insipidus, familial adrenocorticotropic hormone (ACTH) resistance, hypergonadotropic ovarian dysgenesis, familial male precocious puberty, male pseudohermaphroditism, sporadic hyperfunctional thyroid nodules, familial nonautoimmune hyperthyroidism, familial hypothyroidism, familial hypocalciuric hypercalcemia/neonatal severe primary hyperparathyroidism, familial hypoparathyroidism, congenital bleeding, Hirschsprung disease, Jansen metaphyseal chondrodysplasia, and familial growth hormone deficiency (Spiegel, supra). A G-protein controlled pathway, the β-adrenoreceptor/adenylate cyclase pathway, appears to be desensitized in heart failure (Meij, supra).
G protein-coupled receptors (GPCRs) play a major role in signal transduction and are targets of many therapeutic drugs. The regulator of G protein signaling (RGS) proteins form a recently identified protein family (See e.g., DeVries et al., Ann Rev Pharmacol 40:235 [2000]; Ross and Wilkie, Ann Rev Biochem 69:795 [2001]). RGS proteins strongly modulate the activity of G proteins. Their best-known function is to inhibit G protein signaling by accelerating GTP hydrolysis (GTPase activating protein (GAP)) thus turning off G protein signals. RGS proteins also possess non-GAP functions, through both their RGS domains and various non-RGS domains and motifs (e.g., GGL, DEP, DH/PH, PDZ domains and a cysteine string motif). They are a highly diverse protein family, have unique tissue distributions, are strongly regulated by signal transduction events, and play diverse functional roles in living cells.
Thus, effective modulators of G-protein signaling for use in the treatment of G-protein mediated pathologies are needed.